IADR Abstract Archives
Glucan 1,3-betaglucanase of Candida albicans as a Novel Antifungal Target
Objectives: Candida albicans is the major fungal pathogen in humans which affects a large number of compromised host populations including HIV-infected patients, renal transplant recipients, cancer patients and critically ill patients. Currently, only a few antifungal agents are available for the treatments of C. albicans infections. In addition, the emergence of multi-drug resistant strains, drug-related toxicity, and high treatment cost have limited their use. In the present study, we explored the target of a novel small molecule SM21 which possess promising antifungal activity using in silico and in vitro approaches.
Methods: Virtual target screening was performed for SM21 in silico using SMILES (Simple molecular input line entry system) from PubChem and drug discovery tool from Mcule (https://mcule.com). Compound-target interaction was calculated with AutoDock Vina docking algorithm. Compound target interactions with higher binding affinity were selected for 3D visualization. Antifungal susceptibility test was performed for C. albicans XOG1 double knockout strain, XOG1 recombinant strain and XOG1 overexpression strain compared to the parent SC5314 strain using standard methodologies. Furthermore, additional potential targets were predicted using DR. PRODIS. GO term enrichment was carried out for 279 predicted targets using Candida genome database.
Results: In silico data indicated that SM21 interacts strongly with glucan 1,3-betaglucosidase (a negative free energy score 9.8). Antifungal sensitivity assays revealed that overexpression of XOG1 enhanced the susceptibility of C. albicans to SM21 confirming in silico binding affinity results. Filamentous growth and stress response pathways were predicted to be perturbed by SM21. Gene Ontology enrichment revealed that membrane (GOID: 16020) (corrected p-value = 2.54E-10, FDR = 0) and “dolichyl-phosphate-mannose-protein mannosyltransferase activity” (GOID: 4169) (corrected p-value = 0.002, FDR = 0) are significantly enriched.
Conclusions: Foregoing studies have given substantial evidence on the molecular target and pathways affected by SM21, which will provide a strong foundation for further development of this novel antifungal agent.
Methods: Virtual target screening was performed for SM21 in silico using SMILES (Simple molecular input line entry system) from PubChem and drug discovery tool from Mcule (https://mcule.com). Compound-target interaction was calculated with AutoDock Vina docking algorithm. Compound target interactions with higher binding affinity were selected for 3D visualization. Antifungal susceptibility test was performed for C. albicans XOG1 double knockout strain, XOG1 recombinant strain and XOG1 overexpression strain compared to the parent SC5314 strain using standard methodologies. Furthermore, additional potential targets were predicted using DR. PRODIS. GO term enrichment was carried out for 279 predicted targets using Candida genome database.
Results: In silico data indicated that SM21 interacts strongly with glucan 1,3-betaglucosidase (a negative free energy score 9.8). Antifungal sensitivity assays revealed that overexpression of XOG1 enhanced the susceptibility of C. albicans to SM21 confirming in silico binding affinity results. Filamentous growth and stress response pathways were predicted to be perturbed by SM21. Gene Ontology enrichment revealed that membrane (GOID: 16020) (corrected p-value = 2.54E-10, FDR = 0) and “dolichyl-phosphate-mannose-protein mannosyltransferase activity” (GOID: 4169) (corrected p-value = 0.002, FDR = 0) are significantly enriched.
Conclusions: Foregoing studies have given substantial evidence on the molecular target and pathways affected by SM21, which will provide a strong foundation for further development of this novel antifungal agent.